DE2604698A1 - METHOD FOR PRODUCING PHENYLPROPANDIOL GLYCOCOLLE STARS - Google Patents

Description

, DR. STEPHAN G. BESZEDES PATENT ADVOCATE

806 DACHAU near MÖNCHEN

BOX 1168

AM HEIDEWEG 2

TELEPHONE: DACHAU 4371 Postal checking account Munich (BLZ 700 100 80)

Account no. 1368 71

Bank account no. 90 637 at the district and town • psrkasae Dachau-Indersdorf (bank code 700515 40)

P 886

Description

for patent application

EGYT GYOGYSZERVEGYESZETI GYAR

Budapest, Hungary

"concerning

Process for the preparation of phenylpropanediol glycoco hesters

The invention "relates to a new method of manufacture of phenylpropanediol glycoll esters of the general formula

60983A / 0978 - 2 ORIGINAL INSPECTE

7 \\

OH H μ «^ C ^ ^ ^- Cj 0 ^Η 2 Il σ - ( - C H N-C-CC ^ Cl Il I HIGH ^S C1

• HY

X stands for a nitro or methyl sulfonyl group and

Y means an acid residue
as well as their salts.

These compounds have valuable antibiotic effects. There are several methods of making such compounds known.

According to British patents 839 533, 936 365 and 936 366, the compounds of the formula I can be prepared in such a way that a compound of the general formula

609834/0978

f / \

OH H

I I

C-C-C-OH

H N-C-C

Cl Cl

HIGH

wherein X is as defined above, is reacted with chloroacetyl chloride, the resulting chloroacetic acid ester in Acetonitrile is brought to reaction with urotropin and the urotropin complex thus obtained in ethanol with a Mineral acid is implemented. The final product thus obtained crystallizes along with a considerable amount Ammonium chloride (1 mole of final product with 5 moles of ammonium chloride), because of the similar solubilities of these two compounds the purification of the crude product can only be carried out with great difficulty and with high losses. The yield is only 25 to 33%. This process also has other disadvantages. Of these, it should first be emphasized that the reaction in the very corrosive chloroacetyl chloride in a high amount of toxic, flammable and explosive acetonitrile. Moreover, the end product can only be achieved with the help of complicated process engineering stages can be obtained.

In the Austrian patent specification 244 934 there is a process in which a compound of the formula II, in which X stands for a methylsulfonyl group, is in a ball mill for 110 hours with glycyl chloride hydrochloride

609834/0978

■ is implemented, described. That in a yield of
47% of the product obtained has a melting point of
184 to 185 ° C. It should be mentioned as a significant disadvantage of this method that a special device is required to carry it out. Furthermore, the glycyl chloride hydrochloride used as the starting substance is a compound that is difficult to access and manufacture and is not easy to handle. Besides, the yield is in spite of the
110 hours of reaction time is only moderate and the degree of purity of the product obtained is also unsatisfactory, which is reflected in its melting point, which is around
5 to 6 ⁰ C lower than the melting point of the pure product is expressed.

From the French patent 1 488 658 a process for the preparation of compounds of the formula I is
in which χ stands for a methylsulfonyl group, according to
which the corresponding phenylpropanediol derivative with
N-Carbobenzyloxyglykokoll acylated in the presence of either triethylamine and pivaloyl chloride or dicyclohexylcarbodiimide and then the carbobenzyloxy group either with the aid of trifluoroacetic acid or
is removed by catalytic hydrogenation is known. The product obtained in an overall yield of 72% has a melting point of 184 to 185 ° C. This process, too, has numerous disadvantages which practically preclude it from being carried out on an industrial scale. The degree of purity of the product
namely, it is unsatisfactory for pharmaceutical purposes without further purification. Also, on the basis of experiments by the applicant, the yield is considerably lower than the value of 72% given in French patent 1,488,658 or the removal of the
Carbobenzyloxy protecting group by catalytic hydrogenation
practically none because of the large number of side reactions

609834/0978

feasible. Furthermore, carrying out the reaction because of the use of toxic starting materials and auxiliary substances (such as dicyclohexylcarbodiimide and trifluoroacetic acid) impeded considerably. ¹

In the German Offenlegungsschrift 2 327 648, a process is released according to which acetoacetic ester aminoglycoll is released from its sodium salt with anhydrous pyridine hydrochloride in dimethylformamide and the free acid is reacted with a phenylpropanediol derivative of the formula II, in which X stands for a methylsulfonyl group, in the presence of dicyclohexyl condensation agent , whereupon the dicyclohexylurea is removed and the reaction mixture is poured into water, the amount of water being 120 times greater than that of the compound of formula II, and the product is filtered off, dried and hydrolyzed with a mixture of methanol and hydrochloric acid at the boiling point described. The product obtained in a yield of 95 * 4 x% has a melting point of 188 to 19O ⁰ C. A serious disadvantage of this method is that the acid of the sodium salt of Acetessigesterenaminoglykokolles in a gentle V must be else released so / that it no water is introduced into the system, otherwise the condensation with dicyclohexylcarbodiimide cannot be carried out (therefore anhydrous pyridine hydrochloride must be used). Since at the end of the condensation the product is precipitated by pouring it into 120 times the amount of water, the specific utilization of the device is poor. Furthermore, according to the applicant's experiments, the hydrolysis of the intermediate product cannot be carried out in the manner described. The hydrolysis gives the product only in a yield of 37 »5%. By means of thin-layer chromatographic investigations it was found that the product is not uniform and contains a foreign substance; the product,

609834/0978 ~ ⁶ ~

2604638

which precipitates from the mother liquor after "prolonged standing" at a temperature below ⁰ ° C. is again a mixture of 5 substances, the amount of which represents 15% of the theoretical yield. The mother liquor contains in an amount of 46 "to 4-8% , based on the total amount of product, substances that cannot be obtained and are not compounds of the formula I. The degree of purity of the product was investigated by thin-layer chromatography using a mobile phase consisting of a mixture of butanol, glacial acetic acid and water in a ratio of 60:15:25.

From J. Am. Chem. Soc. 7j> [1951], 3 5 ^ 7 and 89 [1967], 5,012-5,017 is a method of acylating with the aid of mixed ones formed with carbonic acid monoesters Anhydrides, after which a tertiary ammonium salt of the protected amino acid in homogeneous solution with an alkyl chloroformate is implemented, known. The mixed anhydride forms within 5 to 15 minutes and the reaction temperature changes between -10 and -18 ° C. The component to be acylated, which is generally a Is amino acid, is added to this solution. As a tertiary amine for the formation of the tertiary ammonium salt of the protected Amino acid serves mostly triethylamine or one of the type of N-methylpiperidine respectively N-methylmorpholine.

The invention is based on the object of a method by which, while eliminating the disadvantages of the known Process the phenylpropanediol glycollester of the formula I from easily accessible starting substances simple, economical, can be produced in good yields and in high purity.

Surprisingly, the above task has now been carried out

609834/0978

solved the invention.

The invention relates to a process for the preparation of phenylpropanediol glycocollesters of the general type formula

ι /

OH H C - C. 0 H I. ^H 2 Il σ - σ - ) - C C - C. Il • 01 H 0 ^N C1 N - I. H

. HY

X stands for a nitro or methylsulfonyl group and

Y means an acid residue "

as well as their salts by esterifying a phenylpropanediol derivative the general formula

609834/0378

OH H

C-C-C-OH

HIGH

wherein X is as defined above, treating the reaction mixture with water and hydrolysing the product with a Acid, which is characterized in that the phenylpropanediol derivative of the formula II simultaneously with an amino acid salt of the general formula

Alk -OCCN
H ₂

III,

H, C -C = C-C-E

H 0

Alk represents an alkali metal atom

and

R is an alkyl radical with 1 to 3 carbon atoms

- 9 -

609834/0978

or a group of the general formula

- O - R ¹ V,

in which the latter R ^{1 represents} an alkyl radical with 1 to 3 carbon atoms,

means,
and an alkyl chloroformate of the general formula

Il

Cl-C-O-R.

wherein R ^, for an alkyl radical, preferably having 1 to 18, in particular 1 to 3, carbon atoms, is reacted in a heterogeneous system, advantageously in a solvent, optionally in the presence of a diluent, and after the subsequent treatment of the reaction mixture with water formed organic phase, preferably is preferably reacted at a temperature of -10 to +50 ⁰ C without separating the product, with an organic or inorganic acid of the general formula III wherein Y is as defined above.

The molar ratio of the reactants can be varied within wide limits. It is beneficial to the connections of formulas II, HE and IV in molar ratios of. 1: (1 to 2): (1 to 2), preferably 1: 1: 1, to use.

- 10 -

609834/0978

2804698

It is preferred to use sodium or potassium as the alkali metal for which Alk in the formula III is used. Of the alkyl chlorine acid esters of the formula IY can the ethyl chloroformate can be used particularly advantageously.

As the solvent, any organic solvent inert from the viewpoint of the reaction, which Phenylpropanediol derivative of the formula II dissolves and is water-soluble lsi; j used; be, whereby it is advantageous also with Thinners should be infinitely miscible. Such solvents are, for example, dimethylformamide, Dimethyl sulfoxide, tetrahydrofuran and dioxane. Advantageously, a polar aprotic (aprotic) Solvent used. The use of dimethylformamide or dimethyl sulfoxide is preferred.

Compounds which are miscible with the solvents and the alkyl chloroformates can be used as diluents of formula IV, but are only slightly or not at all miscible with water and the Do not dissolve amino acid salts of the formula III. For this purpose, advantageously, if necessary halogen-substituted aromatic hydrocarbons, for example benzene, toluene, xylene, [decahydronaphthalene and chlorobenzene, benzene being preferred, or, optionally halogen-substituted, aliphatic hydrocarbons, for example dichloroethane, dichloromethane, trichlorethylene, chloroform and carbon tetrachloride, with dichloroethane is particularly preferred is used.

The undesired by-products are removed by treating the reaction mixture with water. That desired product is in the from organic

- 11 609834/0978

Solvent "or diluent formed organic phase, which, preferably at a temperature of -10 to +50 ⁰ C, in;
treated with an acid.

rature from -10 to +50 ⁰ C, in particular 0 to 20 ⁰ C, with

In view of the reaction, a particularly low temperature plays, that is a lower temperature than ⁰ ° C. "no decisive role, the reaction rate is, however, at lower temperatures, of course, lower. At temperatures above +50 ⁰ C occur side reactions to a greater extent what is understandable on the basis of the structure of the end products. The reaction can be carried out within a very wide temperature range without significantly affecting the yield. It is preferred to carry out the reaction at temperatures of -20
to lead.

from -20 to +45 ⁰ C, in particular -5 to +20 ⁰ C, through

The compounds of the formula III can be prepared in a manner known per se, for example according to the method described in Revue Roumaine de Ohimie (Ij? p97O], 1 375) have been.

The main advantages of the method according to the invention are as follows:

a) The starting materials are only easily accessible or can be produced in good yields needed.

b) No particularly toxic reactants are required.

. - 12 -

609834/0978

c) The reactive alkyl chloroformate does not have to be prepared separately, because this ester reacts with the phenylpropanediol derivative in situ and through the The heterogeneity of the system ensures a satisfactory reaction rate is.

d) The desired product will be in very high and in some cases in quantitative yields and obtained with a high degree of purity.

The process according to the invention is explained in more detail by means of the following examples, which are not to be interpreted as limiting explained.

example 1
Thiophenicol glycinate hydrochloride

There were 1,500 cet of anhydrous dichloroethane, 247.8 g (1.1 mol) of the potassium salt of acetoacetic ester aminoglycocoll, 260 cnr anhydrous dimethylformamide and Put 365.2 g (1.0 mol) of thiophenicol in one equipped with a stirrer, dropping funnel, thermometer and bubble counter Reaction device introduced. The reaction mixture was cooled to a temperature below -3 ° 0 while stirring, whereupon 108.5 g (1.0 mol) of ethyl chloroformate were added. The evolution of carbon dioxide gas continued within a few Minutes a. The cessation of gas evolution indicated the end point of the reaction. Then the reaction mixture was with Washed 2 χ 45 cmr of water, after which the dichloroethane phase concentrated with stirring at -5 ° C cLie calculated amount

- 13 609834/0978

Hydrochloric acid was added. The precipitated crystals were filtered off and dried to constant weight.

Yield: 4-32 g (96.5% of theory). Melting point: 193 "C. to ⁰ 194- ^{0" value = +11} ° ^ ^{0 = 5i} water).

Example 2
a) Chloramphenicolacetoacetic ester aminoglycinate

The procedure described in Example 1 was followed, but with the difference that the following starting substances used: 100 g (0.31 mol) chloramphenicol, 4-65 cm anhydrous dichloroethane, 76.4 g (0.34-1 mole) of the potassium salt of acetoacetic ester aminoglycocoll, 112 cnr anhydrous Dimethylformamide and 34.6 g (0.31 mol) of ethyl chloroformate .

After washing the reaction mixture with water, the organic phase was cooled and the precipitated Crystals were filtered off.

Yield: 144.6 g (9% of theory). Melting point: 184 to 187 ° C.

b) chloramphenicol glycinate hydrochloride

4.92 g (0.01 mol) of the same as under point a) above described obtained Chloramphenikolacetessigesterenaminoglycinates were dissolved in 20 cbt ethanol and at room temperature with an equivalent amount of hydrochloric acid

609834/0978

containing ethanol implemented.

Yield: 4 g (96.5% of theory). • Melting point: 184 to 185 ° C (melting point after

Literature: 180 to 181 ° C)

Lr \ PO O /

⁰ SJt) value = +20 (c = 5; water).

c) chloramphenicol glycinate acetate

4.92 g (0.01 mol) of the chloramphenikolacetessigesterenaminoglycinate obtained as described under point a) above were reacted in 20 cur ethanol at 40 ⁰ G with 0.66 g of acetic acid.

Yield: 2.28 g (52% of theory). Melting point: 74 to 76 ⁰ C (equal to the value given in literature)

d) Ohloramphenicol glycinate sulfate

4- »92 g (0.01 mol) of the chloramphenikolacetessigesterenaminoglycinate obtained v / ie under the above point a) were reacted in 20 cnr ethanol at -10 ⁰ G with 0.98 g of concentrated sulfuric acid.

Yield: 3.55 S (7 ^ -} 5% of theory). Melting point: 139 to 142 ^° G (equal to the value given in literature).

- 15 609834/0978

Example 3 Thiophenicol glycinate hydrochloride

The procedure was as described in Example 1, but with the difference that instead of the ethyl chloroformate 94.5 g (1 »O mol) of methyl chloroformate were used.

Yield: 321 g (71.6% of theory). Melting point: 193 to 194- ⁰ C.

= 10.95 ° (c - 5; water).

Example 4- Thiophenicol glycinate hydrochloride

The procedure was as described in Example 1, but with the difference that instead of the dimethylformamide 350 cur dimethyl sulfoxide were used.

Yield: 311.9 g (69.6% of theory). Melting point: 194- 192 to ⁰ C. p ^s 10.5 ° (c = 5, water).

Example 5 Thiophenicol glycinate hydrochloride

There were 3.65 g (0.01 mol) of thiophenicol, 12 cur dimethylformamide and 2.4-7 g (0.011 mol) of the potassium salt

- 16 609 8 3 4/0978

of Acetessigesterenaminoglykokoll introduced into a container provided with a stirrer, dropping funnel, thermometer and bubble counter piston and, with vigorous stirring at -1O ⁰ C 1.085 g (0.01 mol) of ethyl chloroformate was added. The reaction was over in a few hours. then

the reaction mixture was poured into 120 cn water and extracted with 3 x 10 cn dichloromethane. The United Dichloromethane solutions were treated at 20 ° C. with ethanol containing the calculated amount of hydrochloric acid. the Crystals were filtered off after standing for 2 hours and dried to constant weight.

Yield: 3.2 g (72% of theory). Melting point: 195 ° C.

^ ⁰ value = + 35 ° (c = 1; methanol).

Example 6
a) Thiophenicolacetoacetic ester aminoglycinate

The procedure was initially as described in Example 1, but with the difference that instead of the

7th

Add dichloroethane 1,500 cnr chlorobenzene to the reaction apparatus were introduced. After the end of the reaction, the reaction mixture was washed with water, whereupon the product initially separated itself in the form of an oil, which however later solidified.

Yield: 506 g (96.5% of theory). Melting point: 99 to 101 ⁰ C.

- 17 -609834/0978

- 17 b) Thiophenicol glycinate hydrochloride

The thiophenicolacetoacetic ester aminoglycinate obtained as described under point a) above was implemented analogously as described in Example 2, part b). The product obtained had the same characteristics as that of des Example 1.

Example 7 Thiophenicol glycinate hydrochloride

The procedure was as described in Example 1, but with the difference that instead of the dimethylformamide 300 car of dimethylacetamide were used.

Yield: 390 g (87% of theory). Melting point: 195 ⁰ O.

| c *] p ^O value - + 30 ° (c = 1; methanol).

Example 8 Thiophenicol glycinate hydrochloride

The procedure was as described in Example 1, but with the difference that instead of the potassium salt the following substances were used by acetoacetic ester aminoglycoll:

- 18 609834

- is -

a) 230 g (1.1 mol) of the sodium salt of Acetoacetic ester aminoglycocoll.

Yield: 336 g (7% of theory). Melting point: 190 to 191 ⁰ C.

= 10.7 (c = 5; V / water).

b) 214.8 g (1.1 mol) of the potassium salt of acetylacetone aminoglycocoll.

Yield: 430 g (96% of theory). Melting point: 1 ^ to 194 ⁰ O.

»11 ° (c = 5; water).

Patent claims 609834/0973

Claims (2)

- 19 claims Process for the preparation of phenylpropanediol glycol esters the general formula OH H I! G-C -C-O-Ho C-C H N-G-C . HY wherein X stands for a nitro or methylsulfonyl group and Y means an acid residue as well as their salts by esterifying a phenylpropanediol derivative the general formula - 20 - 609834/0978 OH H I I C-C-C-OH H _n H N-C-C II Il HIGH wherein X is as defined above, treating the reaction mixture with water and hydrolyzing the Product with an acid, characterized in that the phenylpropanediol derivative of the formula II at the same time with an amino acid salt of the general formula Alk -0-CCN H ₂ III, H _x G -CCCR HO Alk represents an alkali metal atom and R is an alkyl radical with 1 to 3 carbon 609834/0978 - 21 - atoms or a group of the general formula - O - R ' in the soft latter R ^{1 represents} an alkyl radical with 1 to 5 carbon atoms, means, and an alkyl chloroformate of the general formula Il - σι - σ - o - r " where R _{x is} an alkyl radical, preferably with 1 to 18, in particular 1 to 3j carbon atoms, is reacted in a heterogeneous system, advantageously in a solvent, optionally in the presence of a diluent, and which is formed after the subsequent treatment of the reaction mixture with water organic phase, preferably without separating off the product, with an organic or inorganic acid of the general formula HY, in which Y is as defined above, preferably at a temperature of -10 to +50 ⁰ C, is reacted. 2.) Method according to claim 1, characterized in that - 22 609834/0978 that the solvent is a polar, aprotic and water-miscible solvent is used. 3 ·) · Method according to claim 1 or 2, characterized in that that the solvent used is dimethylformamide or dimethyl sulfoxide. 4 ·.) Process according to Claims Λ to 3 », characterized in that an, optionally halogen-substituted, aliphatic hydrocarbon, in particular dichloroethane, is used as the diluent. 5 ·) Method according to claim 1 to 3 »characterized in that that the diluent used is an, optionally halogen-substituted, aromatic Hydrocarbon, especially benzene, is used. 609834/0978